tbuckley/cabot-search huggingface dataset:
Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases
Authors: Florian J. Wopperer, Karl X. Knaup, Kira J. Stanzick, Karen Schneider, Tilman Jobst-Schwan, Arif B. Ekici, Steffen Uebe, Andrea Wenzel, Stefan Schliep, Carsten Schürfeld, Randolf Seitz, Wanja Bernhardt, Markus Gödel, Antje Wiesener, Bernt Popp, Klaus J. Stark, Hermann-Josef Gröne, Björn Friedrich, Martin Weiß, Nikolina Basic-Jukic, Mario Schiffer, Bernd Schröppel, Bruno Huettel, Bodo B. Beck, John A. Sayer, Christine Ziegler, Maike Büttner-Herold, Kerstin Amann, Iris M. Heid, André Reis, Francesca Pasutto, Michael S. Wiesener
Journal: Kidney International (2022)

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.
Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiency
Authors: Stefania Drovandi, Beata S. Lipska-Ziętkiewicz, Fatih Ozaltin, Francesco Emma, Bora Gulhan, Olivia Boyer, Agnes Trautmann, Hong Xu, Qian Shen, Jia Rao, Korbinian M. Riedhammer, Uwe Heemann, Julia Hoefele, Sarah L. Stenton, Alexey N. Tsygin, Kar-Hui Ng, Svitlana Fomina, Elisa Benetti, Manon Aurelle, Larisa Prikhodina, Michiel F. Schreuder, Mansoureh Tabatabaeifar, Maciej Jankowski, Sergey Baiko, Jianhua Mao, Chunyue Feng, Cuihua Liu, Shuzhen Sun, Fang Deng, Xiaowen Wang, Stéphanie Clavé, Małgorzata Stańczyk, Irena Bałasz-Chmielewska, Marc Fila, Anne M. Durkan, Tanja Kersnik Levart, Ismail Dursun, Nasrin Esfandiar, Dorothea Haas, Anna Bjerre, Ali Anarat, Marcus R. Benz, Saeed Talebi, Nakysa Hooman, Gema Ariceta, Franz Schaefer, Sergey Baiko, Lina Maria Serna Higuita, Franz Schaefer, Agnes Trautmann, Mansoureh Tabatabaeifar, Alaleh Gheissari, Nakysa Hooman, Elisa Benetti, Francesco Emma, Nazym Nigmatullina, Beata S. Lipska-Ziętkiewicz, Irena Bałasz-Chmielewska, Marcin Tkaczyk, Małgorzata Stańczyk, Halina Borzecka, Alexey N. Tsygin, Larisa Prikhodina, Radovan Bogdanovic, Ali Anarat, Fatih Ozaltin, Sevgi Mir, Svitlana Fomina, Thomas Klopstock, Holger Prokisch, Cornelia Kornblum, Hong Xu, Qian Shen, Jia Rao, Cui-Hua Liu, Shu-Zhen Sun, Fang Deng, Yang Dong, Xiao-Wen Wang, Jiang-Wei Luan
Journal: Kidney International (2022)

Primary Coenzyme Q10 (CoQ10) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ10 biosynthesis leading to multidrug-resistant nephrotic syndrome as the hallmark kidney manifestation. Promising early results have been reported anecdotally with oral CoQ10 supplementation. However, the long-term efficacy and optimal prescription remain to be established. In a global effort, we collected and analyzed information from 116 patients who received CoQ10 supplements for primary CoQ10 deficiency due to biallelic pathogenic variants in either the COQ2, COQ6 or COQ8B genes. Median duration of follow up on treatment was two years. The effect of treatment on proteinuria was assessed, and kidney survival was analyzed in 41 patients younger than 18 years with chronic kidney disease stage 1-4 at the start of treatment compared with that of an untreated cohort matched by genotype, age, kidney function, and proteinuria. CoQ10 supplementation was associated with a substantial and significant sustained reduction of proteinuria by 88% at 12 months. Complete remission of proteinuria was more frequently observed in COQ6 disease. CoQ10 supplementation led to significantly better preservation of kidney function (5-year kidney failure-free survival 62% vs. 19%) with an improvement in general condition and neurological manifestations. Side effects of treatment were uncommon and mild. Thus, our findings indicate that all patients diagnosed with primary CoQ10 deficiency should receive early and life-long CoQ10 supplementation to decelerate the progression of kidney disease and prevent further damage to other organs.
A novel endoscopic technique for closure of two gastro-gastric fistulas in a single session using an endoscopic helix tacking device
Authors: Lidor Akavia, Iris Dotan, Gerard Aguila, Steven Shamah
Journal: Endoscopy (2022)

A gastro-gastric fistula is a rare but well-known complication of Roux-en-Y gastric bypass surgery, which can lead to weight regain and ulceration [1]. Most commonly, surgical approaches are used to repair such defects [2]; however, endoscopic repair methods have also been used with various success rates [3]. We report the first case of the endoscopic closure of multiple gastro-gastric fistulas in a single session, using an X-Tack Endoscopic HeliX Tacking System (Apollo Endosurgery, Inc., Austin, Texas, USA).
Immunoglobulin-free strategy to prevent HBV mother-to-child transmission in Cambodia (TA-PROHM): a single-arm, multicentre, phase 4 trial
Authors: Olivier Segeral, Bunnet Dim, Christine Durier, Sovann Nhoueng, Kearena Chhim, Saren Sovann, Sophal Yom, Chanlina Vong, Song Yin, Bandith Ros, Vutha Ky, Sothy Pech, Bunthoeun Nem, Kay Hout, Julia Guillebaud, Eamkim Ear, Layana Caroupaye-Caroupin, Claire Rekacewicz, Laura Fernandez, Denis Laurent, Chantana Yay, Rattana Kim, Laurence Meyer, Samsorphea Chhun, Chanthy Keang, Ousa Khan, Boraneath Nang, Vouch Leang Sreng, Sopheavet In, Sineath Sun, Linda Sov, Bunrachana Nor, Brembrey Hing, Sokkim Seng, Sophea Soum, Leakhena Say, Sao Sarady Ay, Daneth Thol, Chhorn Chhouk, Patrice Piola, Janin Nouhin, Anne-Marie Roque Afonso, Jean Charles Duclos Vallee, Channa Sann, Leang Sim Kruy, Maud Lemoine, Laurent Mandelbrot, Stephane Blanche, Alpha Diallo, Christelle Paul, SAY Tiv, Polinn Sar, Lyvoin Nov, Darapoline Vann, Tha Chea, Bunrith Touch, Kongkea Neav, Ekvitou Kong, Ratha Chea, Chanksolina Ouk, Lyhour Meak, Rayounette Krouch, Naneth Chhan, Sody Seang, Veasna Nuon, Leang Meng, Sok Leakhena Tharith, Sovannara Hang, Vanrithy Som, Rithy Som, Phirak Seng, Malys Lim, Kimchhorn Srey, Sok Rothavy Uch, Pichthyda Hou, Satha Bo, Eanghor Ieang, Kimchhorng Korn, Chan Reatrey Noun, Sokhoeun Soy, Thou Khim, Vutha Sou, Sokha Pol, Samreth Nget, Marina Sun, Phearom Uon, Kim Teng Ya, Kimsreng Lean, Kim Ean Eang, Sophal Ung, Rauin Rith, Charya Mom, Chanthea Keang, Soklyda Sam, Sokneth Chuong, Chanmony Nam, Sophya Khuon, Sidet Cheang, Sopheak Lean, Arnaud Tarantola, Isabelle Fournier, Nicolas Rouveau, Maria-Camila Calvo cortez
Journal: The Lancet Infectious Diseases (2022)
<scp>NLRP6</scp> negatively regulates type 2 immune responses in mice
Authors: Pauline Chenuet, Quentin Marquant, Louis Fauconnier, Ali Youness, Manon Mellier, Tiffany Marchiol, Nathalie Rouxel, Yasmine Messaoud‐Nacer, Isabelle Maillet, Aurélie Ledru, Valérie F. J. Quesniaux, Bernhard Ryffel, William Horsnell, Frédérique Végran, Lionel Apetoh, Dieudonnée Togbe
Journal: Allergy (2022)

Inflammasomes are large protein complexes that assemble in the cytosol in response to danger such as tissue damage or infection. Following activation, inflammasomes trigger cell death and the release of biologically active forms of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome is required for IL-18 secretion by intestinal epithelial cells, macrophages, and T cells, contributing to homeostasis and self-defense against pathogenic microbes. However, the involvement of NLRP6 in type 2 lung inflammation remains elusive.Wild-type (WT) and Nlrp6-/- mice were used. Birch pollen extract (BPE)-induced allergic lung inflammation, eosinophil recruitment, Th2-related cytokine and chemokine production, airway hyperresponsiveness, and lung histopathology, Th2 cell differentiation, GATA3, and Th2 cytokines expression, were determined. Nippostrongylus brasiliensis (Nb) infection, worm count in intestine, type 2 innate lymphoid cell (ILC2), and Th2 cells in lungs were evaluated.We demonstrate in Nlrp6-/- mice that a mixed Th2/Th17 immune responses prevailed following birch pollen challenge with increased eosinophils, ILC2, Th2, and Th17 cell induction and reduced IL-18 production. Nippostrongylus brasiliensis infected Nlrp6-/- mice featured enhanced early expulsion of the parasite due to enhanced type 2 immune responses compared to WT hosts. In vitro, NLRP6 repressed Th2 polarization, as shown by increased Th2 cytokines and higher expression of the transcription factor GATA3 in the absence of NLRP6. Exogenous IL-18 administration partially reduced the enhanced airways inflammation in Nlrp6-/- mice.In summary, our data identify NLRP6 as a negative regulator of type 2 immune responses.
Developing and validating a machine-learning algorithm to predict opioid overdose in Medicaid beneficiaries in two US states: a prognostic modelling study
Authors: Wei-Hsuan Lo-Ciganic, Julie M Donohue, Qingnan Yang, James L Huang, Ching-Yuan Chang, Jeremy C Weiss, Jingchuan Guo, Hao H Zhang, Gerald Cochran, Adam J Gordon, Daniel C Malone, Chian K Kwoh, Debbie L Wilson, Courtney C Kuza, Walid F Gellad
Journal: The Lancet Digital Health (2022)
Mechanisms of CD8+ T-cell failure in chronic hepatitis E virus infection
Authors: Janine Kemming, Swantje Gundlach, Marcus Panning, Daniela Huzly, Jiabin Huang, Marc Lütgehetmann, Sven Pischke, Julian Schulze zur Wiesch, Florian Emmerich, Sian Llewellyn-Lacey, David A. Price, Yakup Tanriver, Klaus Warnatz, Tobias Boettler, Robert Thimme, Maike Hofmann, Nicole Fischer, Christoph Neumann-Haefelin
Journal: Journal of Hepatology (2022)
Predictors of trainers’ proficiency during the learning curve of robot-assisted radical prostatectomy: Results from a multicentric series
Authors: U. Anceschi, A. Galfano, P. Dell'Oglio, C.A. Bravi, L. Luciani, S. Albisinni, L. Misuraca, G. Tuderti, A. Brassetti, M.C. Ferriero, G. Petralia, S. Secco, E. Di Trapani, D. Mattevi, M. Puglisi, R. Mastroianni, A.M. Bove, T. Cai, T. Quackels, G. Malossini, A.M. Bocciardi, G. Simone
Journal: European Urology (2022)
Phase 1/2, open-label, dose-escalation, dose-expansion study of menin inhibitor DSP-5336 in adult patients with acute leukemia with and without mixed-lineage leukemia (<i>MLL</i>)-rearrangement (r) or nucleophosmin 1 (<i>NPM1</i>) mutation (m).
Authors: Naval Guastad Daver, John Affinito, Hongliang Cai, Hanna Dobrowolska, Ken Eguchi, Zijing Zhang, Jay Stoudemire, Akinobu Watanabe, Pablo Martinez, Philip Komarnitsky
Journal: Journal of Clinical Oncology (2022)

TPS7066 Background: DSP-5336, a menin MLL interaction inhibitor, elicited antitumor activity in MLL–r or NPM1m acute leukemia models in vitro and in vivo. An open-label, single-arm, phase 1/2 study (NCT04988555) will evaluate the safety and efficacy of DSP-5336 and determine the recommended phase 2 dose (RP2D) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL). Methods: Patients aged ≥18 y with R/R AML, ALL, or acute leukemia of ambiguous lineage after ≥1 line of standard therapy, ECOG PS 0–2, and adequate organ function are eligible. Patients will receive DSP-5336 twice daily for 28 d/cycle. In phase 1, there will be two parallel escalation cohorts: patients who do not receive concomitant azole antifungal medication and patients who receive antifungal azoles (ie, posaconazole, voriconazole, or fluconazole); 21–30 patients will be enrolled during phase 1 into multiple ascending dose levels. Dose escalation will use a Bayesian logistic regression model. Phase 2 will enroll two arms: R/R AML with MLL –r and R/R AML with NPM1m (10 –20 patients/arm). Patients will be treated at the RP2D to evaluate clinical activity and safety. Clinical trial information: NCT04988555. [Table: see text]
Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-Related Macular Degeneration
Authors: Elvira Agrón, Amitha Domalpally, Catherine A. Cukras, Traci E. Clemons, Qingyu Chen, Zhiyong Lu, Emily Y. Chew, Tiarnan D.L. Keenan
Journal: Ophthalmology (2022)
Mitochondrial division inhibitor 1 (mdivi-1) as a potential pharmacological strategy to prevent vascular restenosis
Authors: G Crespo-Avilan, S Hernandez-Resendiz, C Ramachandra, E Liehn, K Preissner, D Hausenloy
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Singapore National Medical Research Council Background New treatments are needed to prevent post-angioplasty and stent restenosis in coronary artery disease (CAD) and peripheral arterial disease (PAD) patients. Accumulated findings have shown that mitochondrial dysfunction is involved in the pathophysiology mechanisms underlying several cardiovascular conditions, however, in the scenario of vascular remodelling after injury, the role of mitochondrial dynamics is not completely understood. Purpose In this study, we investigate the effect of mdivi-1 on neointimal hyperplasia and plaque development in a wire-induced endothelial injury animal model.­ Methods Using ApoE-/- mice on a background of hyperlipidaemia, we investigated weather in vivo administration of mdivi-1 (1.2mg/kg/d) could reduce atherosclerotic plaque volume, plaque complexity and inflammation in a carotid-wire injury model of neointimal hyperplasia. Also, THP-1 monocytes (T-M) and THP-1-derived Macrophages (T-DM) were stimulated in vitro with LPS + IFN-gamma to induce M1 polarization and then subjected to gene expression and protein analysis in the presence or absence of mdivi-1 (50µM). Transmigration and 3D chemotaxis assays were performed in T-M cells and Human peripheral blood monocytes, to evaluate the effect of mdivi-1 on cell migration in response to M-CSF and MCP-1. Finally, we investigated the effects of Mdivi-1 on mitochondrial respiration using Seahorse assay in T-M and T-DM. Results In vivo treatment with mdivi-1 reduced neointimal hyperplasia by 37% when compared to control, and was associated with a significant decrease of vascular smooth muscle cells and macrophages cell numbers, as well as reduction of the pro-inflammatory mediators TNF-α and ICAM-1 in the plaque. In vitro M1 polarization of T-M and T-DM induced both up-regulation and production of pro-inflammatory mediators and mdivi-1 significantly suppressed this effects. In addition, monocyte chemotaxis response to M-CSF and MCP-1 was significantly reduced in the presence of mdivi-1. Lastly, mdivi-1 reduced oxygen consumption rate in T-M and T-DM, and prevented M1-cell polarization. Conclusions We show that mdivi-1 significantly reduces vessel wall thickness, neointimal hyperplasia, monocyte recruitment, and inflammation after vascular endothelial injury, positioning Mdivi-1 as a potential pharmacological strategy to reduce restenosis following angioplasty and stenting in CAD and PAD patients.
Comparative genomic analysis and its prognostic impact on survival between viral hepatitis-related and non-viral hepatitis intrahepatic cholangiocarcinoma.
Authors: Nai-Jung Chiang, Kien Thiam Tan, Chung-Yu Huang, Ming-Huang Chen, Tai-Jan Chiu, Yan-Shen Shan, Chien-Feng Li, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2022)

4120 Background: Intrahepatic cholangiocarcinoma (IHCC) is hard-to-treat cancer with a high mortality rate worldwide. Hepatitis B virus (HBV) or hepatitis C virus (HCV) is involved in the development of IHCC, especially in Asian countries. Despite rapidly growing genomic profiling studies of IHCC in Western and Eastern populations in recent years, less on genomic heterogeneity of viral hepatitis-related and non-viral hepatitis IHCC been reported. This study aims to provide a comprehensive genomic analysis of IHCC and its prognostic value in IHCC populations with or without viral hepatitis infection. Methods: FFPE tissues from 157 patients with IHCC were subject to next-generation sequencing using the FoundationOne CDx (n = 52) or ACTOnco + comprehensive genomic profiling panels (n = 105). Genomic alterations and features, including single nucleotide variations (SNVs), short insertions and deletions (InDels), copy-number variations (CNVs), fusion genes (only FoundationOne CDx), tumor mutations burden (TMB), and microsatellite instability (MSI) status, were analyzed. The prevalence of genetic mutations and their prognostic values were compared between patients with a history of hepatitis B/C infection (BC; n = 71, 45.2%) and those without hepatitis B/C infection (NBNC; n = 79, 50.3%). Seven patients had no medical record of HBV or HCV infection. Results: The most frequently mutated genes in BC- and NBNC-related IHCC populations were TP53, KRAS, and IDH1. The genetic alternations related to PI3K/AKT/mTOR signaling pathway and copy number gain of receptor tyrosine kinase were relatively dominant in BC-related IHCC. In contrast, the Ras/Raf/MAPK pathway alterations were frequently common in NBNC-related IHCC. In addition, we investigated the correlation between commonly altered genes or pathways and overall survival (OS). Interestingly, the prognostic biomarkers in BC- and NBNC-related IHCC were significantly different. The results showed that TP53 DNA-binding domain (DBD) and TET2 mutations were associated with poor prognosis in BC-related IHCC. On the contrary, CDKN2A deletion and Ras/Raf/MAPK pathway alteration were associated with inferior prognosis in NBNC-related IHCC. However, neither the PI3K/AKT/mTOR signaling alteration nor IDH1/2 mutation affected the OS in BC- or NBNC-related IHCC. Notably, we found that SWI/ SNF complex involved in ARID1A, ARID1B, ARID2, PBRM1, and SMARCA4 alterations exhibited a beneficial prognosis in BC-related IHCC patients, which has not been discussed in previous studies. Conclusions: This study provides comparative genomic profiling between BC- and NBNC-related IHCC and shows genomic heterogeneity and different dominant prognostic biomarkers and activated signaling pathways. Different treatment strategies should be considered in these two subpopulations based on these results.
Hospitalization rate differences among cancer patients on biologics and biosimilars.
Authors: Shirisha Reddy, Wilbur Rutter, William Cavers, Elisea Avalos-Reyes, Kjel Andrew Johnson
Journal: Journal of Clinical Oncology (2022)

e13530 Background: Febrile neutropenia (FN), a severe adverse effect of many cancer treatments, often results in emergency hospitalizations. Granulocyte colony-stimulating factors (G-CSF; filgrastim and pegfilgrastim) have proven efficacy in the prophylaxis of chemotherapy-induced neutropenia and are associated with reducing FN and hospitalizations. Clinical studies have shown that biosimilars are comparable to their originator products; however, no real-world studies on the impact of biosimilar G-CSF on FN hospitalizations exist. We hypothesize that no difference in FN-related hospitalizations between biosimilar and originator biologic G-CSF will occur. Methods: This was a retrospective cohort study of adult patients receiving either biologic G-CSF or biosimilar G-CSF from 5/1/2018 through 4/30/2021. Patients were followed from their initial G-CSF fill during the study period until 30 days following the last dose received. Patients were excluded if they switched exposure groups during the study period or did not maintain eligibility for the duration of follow-up. The primary outcome was FN hospital admission rate between the two groups, defined as any inpatient claims with the primary diagnosis ICD-10 code D70.1 or R50.2. Descriptive statistics and logistic regression were conducted to account for confounding between the groups. Incidence rates were calculated per 1000 person-years of exposure (PY); p-values &lt; 0.05 were considered significant. Results: A total of 13,670 patients met the inclusion criteria, with 6,939 (50.8%) receiving biologic G-CSF. Biosimilar patients were younger (Mean [standard deviation (SD)]: 63.8 [13.4] vs. 65.5 [13.0] p &lt; 0.05), male (40.0% vs. 37.2%; p &lt; 0.05), had more G-CSF claims (Mean [SD]: 5.6 [6.8] vs. 4.5 [4.3]; p &lt; 0.05) and were more likely to utilize a specialty pharmacy (10.1% vs. 4.7%; p &lt; 0.05). Pegfilgrastim was the most common G-CSF medication overall (73.5%); however, filgrastim use was significantly more common in biosimilar patients (43.2% vs. 10.4%; p &lt; 0.05). FN hospitalizations were rare, with 1.1% of patients experiencing an event. No difference in hospitalizations were noted (biosimilars: 1.1%, biologics: 1.0%; p = 0.39). After regression, no factors analyzed were associated with FN-related hospitalizations. Crude FN incidence rates were 45.9 cases per 1000 PY (95% Confidence Interval [CI]: 35.6-56.1 per 1000 PY) among biosimilar patients compared to 37.5 cases per 1000 PY (95% CI: 28.6-46.4 per 1000 PY) among biologic patients, resulting in a rate difference of 8.3 cases per 1000 PY (95% CI: 5.2-22.0 cases per 1000 PY; p = 0.22). Conclusions: In a large real-world analysis, biosimilar G-CSF demonstrated similar effectiveness in preventing FN hospitalization as originator biologic G-CSF agents.